High rates of abnormalities in hysterosalpingography in couples with male factor infertility.

The rate of anatomical abnormalities in infertile couples with obvious male factor is unknown. For this purpose the authors retrospectively analyzed 376 hysterosalpingographies (HSG) of couples with severe male factor. Patients were subdivided into four groups according to the woman's age, and primary or secondary infertility: A--less than 35-years-old, primary infertility, B--less than 35-years-old, secondary infertility, C--35-years-old or more, primary infertility, and D--35-years-old or more, secondary infertility. Overall, abnormalities in HSG were demonstrated in 25.5% of the patients, and in 18, 21, 52, and 40 percent of patients in groups A, B, C and D, respectively. Age was found to be a significant independent risk factor (p < 0.05) while primary or secondary infertility was not. The adjusted odds ratio for woman who were 35-years-old or more to have any abnormalities in HSG were 3.7-fold greater (95% CI 2.2- 6.23), than women who were less than 35-years-old. In conclusion, relatively high rates of female mechanical abnormalities may be found even in infertile couples with obvious male factor and are significantly more prevalent in older women.

Serum retinol-binding protein-4 levels in polycystic ovary syndrome patients undergoing controlled ovarian hyperstimulation for in-vitro fertilization cycle.

AIMS: To determine serum retinol-binding rotein 4 (RBP-4) levels in polycystic ovary syndrome (PCOS) patients undergoing controlled ovarian hyperstimulation (COH) for an in vitro fertilization-embryo transfer (IVF-ET) cycle and the possible correlation to COH variables. PATIENTS AND METHODS: 11 consecutive PCOS patients undergoing our routine IVF flexible multidose gonadotropin-releasing hormone (GnRH)-antagonist protocol. Blood was drawn three times during the COH cycle: (1) day 1 or 2 of menstruation, and prior to gonadotropin administration (Day-S) (Day-S); (2) day of or prior to human chorionic gonadotropin (hCG) administration (Day-hCG); and (3) day of ovum pick-up (Day-OPU). Levels of estradiol and serum RBP-4 were compared among the three time points. Serum RBP-4 was measured with a commercial immunoassay. RESULTS: Results showed significantly lower levels of serum RBP-4 on Day-OPU and Day-hCG than on Day-S. Though significant correlations were observed between serum RBP-4 and body mass index, fasting glucose or glucose to insulin ratio, no correlations were found between serum RBP-4 and IVF treatment variables or pregnancy rate. CONCLUSION: While serum RBP-4 decreases during COH for IVF, there is apparently no correlation of serum RBP-4 levels with IVF treatment variables or outcome.

The possible influence of increased body mass index on the clinical efficacy of standard human chorionic gonadotropin dosage.

OBJECTIVES: To evaluate whether the efficacy of standard (10,000 IU) hCG dosage is BMI dependent. PATIENTS & METHODS: During the study period, body mass index (BMI) was recorded in 261 consecutive women enrolled in our ICSI program. Women in the 90th BMI percentile were compared with those in the 10th percentile. The number and percent of mature metaphase-II (M-II) oocytes were considered as the outcome measure. RESULTS: Mean BMI of the 10th and 90th percentile groups were 18.2 +/- 0.7 kg/m2 (n = 26) and 32.8 +/- 2.2 kg/m2 (n = 27), respectively. There were no differences between the groups in mean patients age, number of gonadotropin ampoules used, mean number of oocytes retrieved or the number and percentage of mature M-II oocytes. CONCLUSIONS: Standard (10,000 IU) hCG dosage is adequate to induce final oocyte maturation in IVF patients regardless of their BMI. This may imply that this hCG dosage is much higher than the dosage that is actually required.

A multicenter validation of computerized tomography models as predictors of non- optimal primary cytoreduction of advanced epithelial ovarian cancer.

AIMS: To compare the validity of four predictive models of preoperative computerized tomography (CT) scans in predicting suboptimal primary cytoreduction in patients treated for advanced ovarian cancer. PATIENTS AND METHODS: Preoperative CT scans of patients with stage III/IV epithelial ovarian cancer who underwent primary cytoreductive surgery at one of four medical centers were reviewed by radiologists blinded to surgical outcome. The validity of each set of CT criteria previously published by Nelson, Bristow, Dowdy, and Qayyum as predictors of suboptimal cytoreduction was assessed. RESULTS: Data of 123 patients were evaluated. Optimal cytoreduction (largest diameter of residual tumor < or =1cm) was obtained in 90 (73.2%) patients. All CT models were able to significantly predict surgical outcome (p<0.02). The respective sensitivity, specificity, and accuracy of the CT models to predict sub-optimal cytoreduction was 64%, 64% and 64% for Nelson's criteria, 70%, 64% and 66% for Bristow's criteria, 79%, 60%, and 65% for Dowdy's criteria, and 67% 57% and 60% for Qayyum's criteria. CONCLUSIONS: Apart from Dowdy's criteria, the accuracy rates of CT predictors of suboptimal cytoreduction in the original cohorts could not be confirmed in this cross validation. This study underscores the difficulty in devising universally applicable selection criteria or models that reliably predict surgical outcome across institutions and surgeons.

The reproducibility of histological parameters employed in the novel binary grading systems of endometrial cancer.

OBJECTIVE: To compare the interobserver reproducibility and prognostic value of the FIGO grading system with the histological parameters employed in the various recently proposed binary grading systems of endometrial cancer. METHODS: Seventy two consecutive stage I endometrioid endometrial carcinomas from hysterectomy specimens were independently graded by two pathologists. Clinical data and outcome were obtained from the patients' records. The following histological parameters were evaluated: FIGO grade (dichotomized to grades 1 and 2 vs. grade 3), nuclear atypia, presence of more than 50% solid growth, diffusely infiltrative rather than expansive growth pattern, presence of tumor cell necrosis, and mitotic count. Interobserver agreement was measured by the kappa (k) statistics. Kaplan-Meier survival analysis, log-rank tests and Cox proportional hazard regression were used to evaluate the equality of survival distributions and to model the overall effects of the various predictor variables on survival. RESULTS: The interobserver reproducibility was as follows: FIGO grade, k=0.65; nuclear atypia, k=0.63; solid growth, k=0.51; infiltrative growth pattern, k=0.38; tumor necrosis, k=0.52; and mitotic index, k=0.44. In the comparison of the Kaplan-Meier curves, the following parameters were associated with a significantly poorer survival: FIGO grade 3, p=0.02; presence of more than 50% solid growth, p=0.01; and a high mitotic index, p=0.01. The other binary histological parameters were not significantly predictive of survival. CONCLUSIONS: The proposed novel binary grading parameters are not advantageous in terms of interobserver reproducibility and prognostic significance over dichotomization to FIGO grades 1 and 2 vs. grade 3. A simple binary grade based solely on presence of more than 50% solid growth has a comparable reproducibility and prognostic value.

Lower uterine segment involvement is associated with adverse outcome in patients with stage I endometroid endometrial cancer: results of a multicenter study.

OBJECTIVE: To quantify the relative risk associated with lower uterine segment involvement (LUSI) on outcome measures in patients with apparent stage I endometroid endometrial cancer. METHODS: A cohort of 769 consecutive patients with endometroid endometrial carcinoma apparent stage I, who underwent surgery in five gynecological oncology centers in Israel; 138 patients with and 631 without LUSI were followed for a median time of 51 months. Local recurrence, recurrence-free and overall survival were compared between the two groups. RESULTS: LUSI was associated with grade 3 tumor (p=0.002), deep myometrial invasion (p<0.001), and the presence of lymphvascular space involvement (p=0.01). There were 22 cases of local recurrences, 40 cases of distal recurrences and 80 patients died. Univariate survival analysis showed that patients with LUSI had trend toward lower regional recurrence-free survival (p=0.09), and significant lower distant recurrence-free survival (p=0.04) and lower overall survival (p=0.002). The Cox proportional hazards model demonstrated a significantly decreased overall survival (HR=2.3; 95% CI 1.3, 3.9; p=0.003) in cases with LUSI. CONCLUSIONS: In patients with apparent stage I endometroid endometrial cancer, the presence of LUSI is a poor prognostic factor, associated with a significantly higher risk of distal recurrence and death. The presence of LUSI warrants consideration when deciding upon surgical staging or postoperative management.

Early endometrial changes following successful implantation: 2 and 3-dimensional ultrasound study.

OBJECTIVE: To study of the possible role of ultrasound (US) measurements of the endometrium in the prediction of IVF outcome. PATIENTS AND METHODS: 28 infertile women underwent US measurements of endometrial thickness and volume on day of ET and two weeks later. US measurements were compared between day of ET and two weeks later, and between those who conceived and those who did not. RESULTS: While in the group of patients who conceived (n = 7) endometrial thickness and volume rose significantly between day of hCG and two weeks later, no differences were observed in patients (n = 21) who did not. CONCLUSION: The dynamic changes in endometrial volume and thickness between day of ET and two weeks later may predict IVF treatment outcome.

Luteal phase support for patients undergoing frozen-thawed embryo transfer cycles--the required progesterone dose.

OBJECTIVE: With the recent trend toward single-embryo transfer (ET), cryopreservation of extraneous embryos is becoming increasingly prevalent. Several replacement protocols for frozen-thawed ET exist, with no consensus regarding the dosage or delivery mode of progesterone. PATIENTS AND METHODS: Hormonal replacement with only estrogen and progesterone is the most frequently used protocol in women with and without functioning ovaries in our unit. Since August 2005, we have doubled the usual daily dose of progesterone for luteal support due to a high prevalence of patients experiencing withdrawal bleeding 11-13 days after ET. We compared the outcome of frozen-thawed ET cycles using different doses of progesterone for luteal support. RESULTS: While the prevalence of embryos that survived the thawing process was significantly higher in the earlier (69%) as compared to the later period (58%), positive b-hCG pregnancy rates (17.5% vs 44.8%, respectively) and clinical pregnancy rates per transfer (7.9% vs 41.4%, respectively) were significantly higher in the later period. CONCLUSION: We conclude that high-dose progesterone supplementation in the luteal phase of frozen-thawed ET cycles results in a significantly higher clinical pregnancy rate.

Mild tricuspid regurgitation: a benign fetal finding at various stages of pregnancy.

OBJECTIVE: Tricuspid regurgitation (TR) may accompany various anatomical malformations and/or dysfunction of the fetal right heart. It may also appear in an anatomically healthy heart. With improved ultrasound modalities, more cases than the previously estimated prevalence of fetal TR in the low-risk population are being diagnosed. The objective of this study was to determine the prevalence of mild fetal TR in a low-risk obstetric population. METHODS: In 157 low-risk pregnant women (age range, 18-42 years) undergoing both early second-trimester and mid-trimester targeted organ scanning, including complete fetal echocardiography according to the five transverse planes technique, the apical four-chamber view was visualized using gray-scale, color Doppler and spatiotemporal image correlation (STIC) ultrasound modalities, with optimal acquisition parameters. RESULTS: Mild-to-moderate TR was discovered in the early second-trimester scan in 131/157 (83.4%) fetuses. No cases of cardiac malformation were found. All fetuses showed normal flow in the ductus venosus, including in one case diagnosed with moderate TR. Only in 39 (24.8%) cases was mild TR still evident at the second, mid-trimester scan. Neonatal echocardiography revealed mild TR in eight (5.1%) cases. No cases of chromosomal anomalies were detected. CONCLUSION: Mild TR is a benign finding of a temporal nature in early pregnancy.

Human placental Hofbauer cells express sprouty proteins: a possible modulating mechanism of villous branching.

The development of the chorionic villous tree into a complex and organized ramified tubular network can be termed branching morphogenesis. Studying the molecular mechanisms involved in this process may contribute to the understanding of pregnancy complications such as preeclampsia. Sprouty (Spry) proteins are important regulators of branching morphogenesis and growth factor signaling. We analyzed the expression of Spry genes in human placenta. RT-PCR and immunohistochemistry were employed to detect placental Spry expression. Quantitative RT-PCR was used to assess the effect of FGF and reduced oxygen fraction on Spry gene expression. Spry 1, 2 and 3 expression was observed in placental tissue from all three trimesters. Our results reveal for the first time that Spry proteins are localized in the stroma of the chorionic villi, adjacent to cytotrophoblasts in areas of villous sprouting. Immunofluorescent double staining with anti-Spry and anti-CD68 confirmed that placental macrophages (Hofbauer cells) express Spry. Reduced oxygen fraction, FGF-4 and FGF-10 stimulated Spry-2 expression. Hofbauer cells also expressed c-Cbl, a protein that interacts with Spry. Placental expression of Spry and c-Cbl implies an important role for Hofbauer cells in placental development, possibly through a mesenchymal-epithelial interaction with trophoblasts. Regulation of Spry-2 expression by FGF-4 and FGF-10 suggests an orchestrated regulatory system that modulates villous branching.

Eph and ephrin expression in normal placental development and preeclampsia.

Eph receptors and their ephrin ligands play a fundamental role in embryogenesis. Their functions include cell targeting and angiogenesis. In placental development, trophoblasts migrate and invade maternal tissue and spiral arteries, where they play a role in both anchoring the placenta to the uterus and increasing blood flow to the developing fetus (interstitial and endovascular invasions). We investigated the cellular distribution and expression patterns of representative Eph and ephrin RNA and protein in an effort to identify the molecules involved in trophoblast migration during normal placental development and placental pathologies. We found ephrin-A1 expressed exclusively in the invasive extravillous trophoblast (EVT) cell lineage. We therefore proceeded to investigate ephrin-A1 in placental pathologies with defects in EVT invasion. In preeclampsia, where trophoblast invasion is shallow, we observed ephrin-A1 expression similar to normal placenta. Furthermore, in initial experiments on the deeply invading trophoblasts of placenta accreta, which lacks decidua, ephrin-A1 is found to be expressed highly in extravillous trophoblasts that have invaded the myometrium. In addition, we found the prototype ephrin-A1 receptor, EphA2, localized in several placental cell types. EphB4 and ephrin-B2 molecules, which have specific expression patterns during artery and vein development, respectively, were also expressed in the placenta. The cell specific distribution of ephrin-A1 suggests that it may play a role in targeting and migration of trophoblasts, and in the vascular remodeling induced by the invading extravillous trophoblasts. Failure of ephrin-A1 expression is unlikely to be the primary cause in defective migration of trophoblasts observed in preeclampsia. Specific roles for other Eph and ephrin proteins remain to be investigated.

Vascular endothelial growth factor, epidermal growth factor and fibroblast growth factor-4 and -10 stimulate trophoblast plasminogen activator system and metalloproteinase-9.

Trophoblast invasion, accompanied by degradation of extracellular matrix, is crucial to normal pregnancy development, whereas shallow placental invasion and implantation likely plays a role in the subsequent development of pre-eclampsia. The growth factors vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and fibroblast growth factor (FGF) are placental growth factors that activate degradation of extracellular matrix. We determined the effect of VEGF, EGF, FGF-2, FGF-4 and FGF-10 on the plasminogen activator system of first trimester cytotrophoblasts cultured in vitro. We studied the activity of urokinase plasminogen activator (uPA), its inhibitor plasminogen activator inhibitor-1 (PAI-1), and 92 kDa gelatinase-B (matrix metalloproteinase-9, MMP-9), using protein gel and reversed gel zymography. The expression pattern of FGF-4 and FGF-10 in human placental sections was determined by immunohistochemistry. FGF-4 was expressed in first trimester villi stroma, primarily in endothelial cells. FGF-10 expression was localized to first trimester extravillous trophoblasts. VEGF, EGF, FGF-4 and FGF-10, but not FGF-2, stimulate the activity of trophoblast uPA, PAI-1 and MMP-9. These results support the hypothesis that specific growth factors modulate the invasive potential of trophoblasts, and therefore may play an important role in early placental development. Our findings may contribute to the understanding of the pathophysiology of diseases associated with shallow placentation, such as pre-eclampsia.

Fetal supraventricular tachycardia diagnosed and treated at 13 weeks of gestation: a case report.

Supraventricular tachycardia (SVT) is the most commonly encountered clinically significant tachycardia in the fetus. When SVT is sustained, congestive heart failure and fetal hydrops may ensue, due to both systolic and diastolic dysfunction. Sonographic diagnosis is usually incidental during the second or third trimester. Treatment goals are cardioversion to sinus rhythm and reversal of cardiac dysfunction. We describe a case of fetal SVT diagnosed at 13 weeks of gestation. Treatment with digoxin and flecainide was successful; the heart rate returned to sinus rhythm within one day, and fetal hydrops resolved within 8 days of treatment. We suspect that as more first-trimester examinations are performed, more cases with SVT will be diagnosed. We discuss the treatment protocol, and suggest that co-administration of two drugs that act synergistically may be more efficient than monotherapy, which is currently used as the first line of treatment. In addition, we discuss the potentially deleterious effect of heart failure encountered at an early developmental stage on the central nervous system. More data need to be collected in order to substantiate a clear recommendation regarding optimal management.

Prenatal ultrasonographic diagnosis of atypical Nonne-Milroy lymphedema.

Nonne-Milroy lymphedema is a relatively rare disorder characterized by firm edema of the lower extremities either on the whole leg or limited to the feet or toes. We report a case of atypical Nonne-Milroy syndrome that presented prenatally with bilateral leg edema, bilateral hydrothorax and lung hypoplasia at 22 weeks' gestation. The differential diagnoses are discussed.

The three vessels and trachea view (3VT) in fetal cardiac scanning.

OBJECTIVE: Comprehensive evaluation of the fetal heart has become a major part of targeted organ scanning to rule out fetal malformations. Evaluation of the mediastinal major vessels seems to be the most difficult and time-consuming part of fetal heart examination. Our aim was to define and evaluate the three vessels and trachea (3VT) view, a novel and simple method to examine the great vessels in the mediastinum, and its applicability in the clinical practice of fetal echocardiography, while establishing nomograms for cardiac vessel measurements obtained in this view. METHODS: The three vessels and trachea view was examined in 379 low-risk gravidae between 14+0 and 23+6 weeks' gestation. Six parameters in this plane were measured to establish nomograms. In another group of 984 mixed high- and low-risk patients we compared the time required to identify the aortic arch using the 3VT view as compared to the long-axis view. RESULTS: The 3VT view was readily and satisfactorily demonstrated in all but two of the 1363 cases examined. In 17 cases (out of a total of 982) more than 10 min were required to identify the aortic arch using the 3VT view and in 71 patients when employing the long-axis view (P < 0.001). CONCLUSION: The clinical applicability of the 3VT view to evaluate the anatomy of the major vessels in the mediastinum is demonstrated. Although a wide variation in the six parameters of the 3VT view used here precludes their use in diagnosing great vessel anomalies, some of the ratios between them have promising potential in the evaluation of great vessel malformations. Further, the 3VT view seems to be more efficient in identifying the aortic arch than does the long-axis view.

Risk of fetal loss in twin pregnancies undergoing second trimester amniocentesis(1).

OBJECTIVE: To assess the rate of fetal loss among bichorionic twin gestations undergoing genetic amniocentesis compared with singletons undergoing the procedure and untested twins. METHODS: In a retrospective cohort study, three groups were compared: 476 women with twins undergoing amniocentesis, 489 women with singleton gestations undergoing amniocentesis, and 477 women with twins presenting at a similar gestational age for ultrasound studies only. All subjects were scanned at 17-18 weeks' gestation and again approximately 4 weeks after the procedure or first ultrasound scan. Excluded were twin pregnancies after fetal reduction or chorionic villus sampling, fetuses with structural anomalies, and cases in which one fetus had died at the time of examination or after fetal reduction. RESULTS: Thirteen twin gestations in the tested group (2.73%) aborted spontaneously up to 4 weeks after the procedure compared with three twin controls (0.63%, P =.01) and three post-procedure singleton controls (0.6%, P =.01). An abnormal karyotype was discovered in 15 tested twin pregnancies (3%) and in six tested singletons (1.23%). All affected twin pairs were discordant for the chromosomal anomaly. CONCLUSION: The risk of early fetal loss in twins undergoing amniocentesis appears to be higher than that of exposed singletons or unexposed twins.

Retinal and intraventricular cerebral hemorrhages in the preterm infant born at or before 30 weeks' gestation.

PURPOSE: To determine the prevalence of retinal hemorrhages and their association with cerebral intraventricular hemorrhages (IVH) in low-birth-weight preterm neonates born at or before 32 weeks' gestation. METHODS: We prospectively studied a consecutive series of 22 neonates (24-30 weeks' gestation; mean gestational age, 27 weeks; mean weight, 1065 g) admitted to the neonatal intensive care unit. Anterior segment and indirect ophthalmoscopic examination, as well as cranial ultrasonographic examination, were performed on day 1 and day 10 of life. The prevalence of retinal and intraventricular hemorrhage was tested statistically for association with obstetric and neonatal clinical variables. RESULTS: The prevalence of retinal hemorrhage was 9% (2/22; 95% CI, 3%-21%) on day 1 and 2% (1/22) on day 10. The prevalence of IVH was 27% (6/22; 95% CI, 9%-46%): 14% (3/22) on day 1 and 23% (5/22) on day 10. Retinal hemorrhages occurred with greater frequency in neonates born to women who had intrauterine infection (chorioamnionitis, P =.043) and low umbilical cord pH levels (P =.027). No association was found between the presence of retinal hemorrhage and IVH (P = 1.000), mode of delivery (ie, vaginal vs cesarean section, P = 1.000), birth weight (P =.476), or gestational age (P = 1.000). The presence of subconjunctival hemorrhage was associated with IVH (P =.046). CONCLUSIONS: Retinal hemorrhages occur in less than 10% of low-birth-weight neonates, ie, a prevalence one half that observed in term neonates (22%). The hemorrhages tend to resolve without sequelae in the first 10 days of life and occur more commonly in infants born to women with uterine infection. Retinal hemorrhages in very premature neonates are not predictive of IVH-related brain damage.

Simultaneous multigate spectral Doppler imaging of the umbilical artery and placental vessels: novel ultrasound technology.

OBJECTIVE: To establish gestational age-specific nomograms of pulsatility indices in the umbilical artery and chorionic and intraplacental vessels, using novel ultrasound technology. STUDY DESIGN: A prospective, cross-sectional study of 160 healthy singleton pregnancies between 18 and 33 weeks of gestation. MEASUREMENTS: Using simultaneous multigate spectral Doppler imaging specialized hardware and software, we measured the flow velocity waveforms of the umbilical artery, chorionic and intraplacental vessels. Computerized automatic mapping calculated the pulsatility indices in regions of interest. RESULTS: Data were adequately obtained for 160 fetuses. The pulsatility index values in the three sites measured decreased with advancing gestational age; the correlation coefficients r = -0.74, r = -0.67 and r = -0.68 for the umbilical artery, chorionic and intraplacental vessels, respectively, were found to be highly statistically significant (p < 0.0001). CONCLUSION: Simultaneous multigate spectral Doppler imaging provides simultaneous measurements of the velocity waveforms in the umbilical artery, chorionic and intraplacental vessels, and is a feasible and reproducible method of obtaining these data. The normal data presented may facilitate early detection of flow disturbances in the fetoplacental circulation.